α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Johannes Levin; Simone Baiardi; Corinne Quadalti; Marcello Rossi; Angela Mammana; Jonathan Vöglein; Alexander Bernhardt; Richard J Perrin; Mathias Jucker; Oliver Preische; Anna Hofmann; Günter U Höglinger; Nigel J Cairns; Erin E Franklin; Patricio Chrem; Carlos Cruchaga; Sarah B Berman; Jasmeer P Chhatwal; Alisha Daniels; Gregory S Day; Natalie S Ryan; Alison M Goate; Brian A Gordon; Edward D Huey; Laura Ibanez; Celeste M Karch; Jae-Hong Lee; Jorge Llibre-Guerra; Francisco Lopera; Colin L Masters; John C Morris; James M Noble; Alan E Renton; Jee Hoon Roh; Matthew P Frosch; C Dirk Keene; Catriona McLean; Raquel Sanchez-Valle; Peter R Schofield; Charlene Supnet-Bell; Chengjie Xiong; Armin Giese; Oskar Hansson; Randall J Bateman; Eric McDade; Dominantly Inherited Alzheimer Network; Piero Parchi

doi:10.1002/alz.13818

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Alzheimers Dement. 2024 Apr 26. doi: 10.1002/alz.13818. Online ahead of print.

Authors

Johannes Levin^{1

2

3}, Simone Baiardi⁴, Corinne Quadalti⁵, Marcello Rossi⁵, Angela Mammana⁵, Jonathan Vöglein^{1

2}, Alexander Bernhardt^{1

2}, Richard J Perrin^{6

7}, Mathias Jucker^{8

9}, Oliver Preische^{8

9}, Anna Hofmann^{8

9}, Günter U Höglinger^{1

2

3}, Nigel J Cairns¹⁰, Erin E Franklin^{6

7}, Patricio Chrem¹¹, Carlos Cruchaga¹², Sarah B Berman¹³, Jasmeer P Chhatwal¹⁴, Alisha Daniels⁷, Gregory S Day¹⁵, Natalie S Ryan^{16

17}, Alison M Goate¹⁸, Brian A Gordon⁷, Edward D Huey¹⁹, Laura Ibanez¹², Celeste M Karch¹², Jae-Hong Lee²⁰, Jorge Llibre-Guerra⁷, Francisco Lopera²¹, Colin L Masters²², John C Morris⁷, James M Noble²³, Alan E Renton²⁴, Jee Hoon Roh²⁵, Matthew P Frosch²⁶, C Dirk Keene²⁷, Catriona McLean²⁸, Raquel Sanchez-Valle²⁹, Peter R Schofield^{30

31}, Charlene Supnet-Bell⁷, Chengjie Xiong³², Armin Giese³³, Oskar Hansson^{34

35}, Randall J Bateman⁷, Eric McDade⁷; Dominantly Inherited Alzheimer Network; Piero Parchi^{4

5}

Affiliations

¹ Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany.
² German Center for Neurodegenerative Diseases, Munich, Germany.
³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
⁵ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
⁶ Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁷ Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁸ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁹ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ Living Systems Institute, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
¹¹ FLENI, Montañeses 2325 (C1428AQK), Buenos Aires, Argentina.
¹² Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.
¹³ University of Pittsburgh Neurology, Pittsburgh, Pennsylvania, USA.
¹⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Department of Neurology, Mayo Clinic in Florida, Jacksonville, Florida, USA.
¹⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁷ UK Dementia Research Institute at UCL, London, UK.
¹⁸ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁹ Butler Hospital, Brown Center for Alzheimer's Disease Research, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²⁰ Department of Neurology, Asan Medical Center, Seoul, South Korea.
²¹ Grupo de Neurosciencias de Antioquia, Sede de Investigación Universitaria SIU, Medellín, Colombia.
²² Florey Institute and The University of Melbourne, Melbourne, Victoria, Australia.
²³ Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and GH Sergievsky Center, Columbia University, New York, New York, USA.
²⁴ Department of Genetics and Genomic Sciences and Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁵ Departments of Neurology and Physiology, Korea University College of Medicine, Seoul, South Korea.
²⁶ MassGeneral Institute for Neurodegenerative Diseases, Neuropathology Service, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁷ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
²⁸ Department of Anatomical Pathology, AlfredHealth, Melbourne, Victoria, Australia.
²⁹ Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clinic de Barcelona, FRCB-IDIBAPS, Barcelona, Spain.
³⁰ Neuroscience Research Australia, Sydney, New South Wales, Australia.
³¹ School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
³² Division of Biostatistics, Washington University School of Medicine, Saint Louis, Missouri, USA.
³³ Modag GmbH, Wendelsheim, Germany.
³⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
³⁵ Memory Clinic, Skåne University Hospital, Lund, Sweden.

PMID: 38666355
DOI: 10.1002/alz.13818

Abstract

Introduction: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.

Methods: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.

Results: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo.

Discussion: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity.

Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Keywords: Dominantly Inherited Alzheimer Network; Lewy body pathology; alpha‐synuclein seed amplification assay; real‐time quaking‐induced conversion.

Abstract

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